Carbonyloxy steroids



United States Patent CARBONYLOXY STEROIDS John A. Hogg, KalamazooTownship, Kalamazoo County, Philip F. Bea], Portage Township, KalamazooCounty, and Frank H. Lincoln, Jr., Kalamazoo Township, Kalamazoo County,Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporationof Michigan No Drawing. Application March 30, 1953,

Serial No. 345,676

Claims. (Cl. 260-23955) This invention relates to a novel class ofcarbonyloxy steroids, more particularly to certain 3-cyclic ketalizedll-oxygenated 21 carbonyloxy-4,l7(20)-pregnadiene- 3-ones. Thisapplication is a continuation-in-part of copending application S. N.307,385, filed August 30, 1952.

It is an object of the present invention to provide novel 3-cyclicketalized 3-keto-ll-oxygenated-4,17(20)-pregnadiene-Zl-oic acids andalkyl esters thereof. Other objects will be apparent to those skilled inthe art to which this invention pertains.

The compounds of the present invention may be prepared and used in theproduction of steroids useful as precursors to cortical hormonesaccording to a series of reactions which may be represented as follows:

wherein R is an a-hydroxy group, a fi-hydroxy group, or a ketonic oxygen(:0), and wherein R, R", and R are hydrogens or alkyl radicalspreferably containing from one to eight carbon atoms, inclusive, i. e.,loweralkyl, and n is the whole number zero or one. The novel compoundsof the present invention may be represented by Formula II above.

According to the method of the present invention, an ll-oxygenated 21carbonyloxy-4,l7(20)-pregnadiene- 3-one (I) is contacted with analkane-a-diol or an alkanefi-diol, i. e., a glycol, in the presence ofan acid catalyst, to produce a 3-cyc1ic ketalizedll-oxygenated-Zl-carbonyloxy-4,17()-pregnadiene-3-one (II) of thepresent invention. The reaction of said ketalized compound with lithiumaluminum hydride in an organic solvent therefor followed by a mildaqueous hydrolysis of any 0 tassium chlorate,

excess lithium aluminum hydride or organo-lithium complexes isproductive of a 3-ketalized 11,21-dihydroxy- 4,l7(20)-pregnadiene-3-one(III). subjecting said latter compound to an aqueous acid hydrolysis isproductive of 11,2l-dihydroxy-4,l7(20)-pregnadiene-3-one (IV) which canbe converted to cortisone or l7-hydroxycorticosterone or esters ofeither of said compounds according to methods illustrated in greaterdetail in copending application S. N. 307,385, filed August 30, 1952.

The compounds represented by Formula I may be named as ll-oxygenated 21carbonyloxy-4,17(20)- pregnadiene-S-ones or as3-keto-11-oxygenated-4,l7(20)- pregnadiene-Zl-oic acids and alkyl estersthereof. Similarly, the compounds represented by Formula II may be namedas 3-cyclic ketalized11-oxygenated-21-carbonyloxy-4,l7(20)-pregnadiene-3-ones or as 3-cyclicketalized 3-keto-1l-oxygenated4,17(20)-pregnadiene-2l-oic acids andalkyl esters thereof.

An 1l,2l-dihydroxy-4,17(20)-pregnadiene-3-one represented by Formula IVwherein the ll-hydroxy group has the beta stereoconfiguration, or a21-ester thereof, is converted to 11,8,17a,21-trihydroxy 4pregnene-3,20- dione (Kendalls Compound F) by reaction with osmiumtetroxide to produce the l1B,l7a,20,21-tetrahydroxy-4- pregnene-3-oneosmate ester, or 2l-ester thereof, and subsequent oxidation thereof, aswith perchloric acid, salts thereof, or other equivalent oxidizing agentsuch as, for example, hydrogen peroxide, dialkyl peroxides, organicperacids such as peracetic acid or perbenzoic acid, po-

or the like, in a solvent such as an ether COOR' III CHzOH or analcohol, e. g., tertiary butyl alcohol or diethyl ether, according tothe procedure already known in the art [Prins and Reichstein, Helv.Chim. Acta, 25, 300 (1942); Ruzicka and Mueller, Helv. Chim, Acta. 22,755 (1939)] Similarly, starting with 1la,2l-dihydroxy-4,l7(20pregnadiene-3-one (IV) and proceeding through the same reactionsdescribed above, and additionally, preferentially oxidizing thell-hydroxy group to an ll-keto group, e. g., by esterifying the2l-hydroxy group of the 11a,17oc,21- trihydroxy-4-pregnene-3,20-dione,obtained in the osmium tetroxide hydroxylation and subsequent oxidationreaction, and then oxidizing the lla-hydroxy group to an 11- keto groupwith chromic acid, produces 17a,21-dihydroxy- 4-pregnene-3,11,20-trione(Kendalls Compound E).

The starting 1l-oxygenated-Z1-carbonyloxy-4,17(20)- pregnadiene-S-onesare prepared by contacting an 11-oxygenated-21,2l-dihalo-2l-carbonylprogesterone sented by the followingformula:

repre- R being a hydrocarbon radical, with a base, e. g., analkali-metal alkoxide, in the presence of hydroxy or alkoxy ions toproduce a startingll-oxygenated-Zl-carbolyloxy-7,l7(20)-pregnadiene-3-one (I) according tothe method illustrated in the preparations hereinafter and as more fullydisclosed in the above-cited copending application.

In carrying out the process of the present invention, a starting steroid(I) described above, is contacted with an alkane-ot-diol or analkane-/3-diol, in the presence of an acid catalyst, at a temperaturefrom about room temperature to the boiling point of the reaction solventemployed, for from about one-half hour to about eighteen hours orlonger, which time being, if the water of the reaction is concomitantlyremoved, the time required to remove about a molar equivalent of waterper mole of steroid from the reaction mixture. Under these conditions,when the starting steroid is a free acid, the acid group may, to acertain extent, be esterified by the alkanediol to produce a glycolester thereof. Treatment of the reaction mixture with aqueous oralcoholic base, preferably an alkali-metal base, and then liberating thefree acid from the thus-produced salt, taking care to avoid hydrolysisof the ketal radical, is productive of essentially pure product (II)wherein R is H, i. e., a free acid.

Alkane-a-diols and alkane-B-diols which may be used include ethyleneglycol, trimethylene glycol, and alkyl-substituted ethylene glycols andtrimethylene glycols, preferably having no more than two alkyl groupssubstituted thereon, e. g., propane-1,2-diol, butane-1,2-diol,S-methylbutanel,2-diol, octane-1,2-diol, butane-2,3-diol, pentane-2,3-diol, 5,S-dimethyloctane-2,3-diol, butane-1,3-diol, pentane 2,4diol, 4-methylpentane-1,3-diol, octane-1,3- diol, and the like.

Acid catalysts which may suitably be employed in the reaction includeanhydrous hydrogen chloride, concentrated sulfuric acid,para-toluenesulfonic acid, benzenesulfonic acid, sulfoacetic acid, andthe like, in amounts from a trace to a substantial fraction of a molarequivalent or greater per mole of steriod.

Reaction solvents which may be suitably employed include hydrocarbonsolvents, halogenated hydrocarbons, ethers, esters, and the like, suchas, for example, benzene, toluene, xylene, hexane, heptane, chloroform,carbon tetrachloride, chlorobenzene, diethyl ether, dioxane,tetrahydrofuran, and others, or an excess of the alkanediol employed.

A suitable method of carrying out the above-described process comprisesdissolving the starting steroid and the selected glycol, preferablyethylene glycol, in the selected solvent, preferably a water-immisciblesolvent, e. g., benzene, toluene, or carbon tetrachloride, andthereafter heating the reaction mixture, in the presence of the reactioncatalyst, at the reflux temperature thereof, with the concomitantremoval of the water formed in the reaction, until about a molarequivalent of water per mole of steroid has been removed from themixture. Reaction times from about one-half hour to several days maysometimes be required to complete the ketalization to a satisfactoryextent.

Isolation of the resulting ketalized steroid (II) is convenientlyachieved by washing the reaction mixture with dilute base, e. g., diluteaqueous sodium bicarbonate, sodium carbonate, potassium hydroxide,methanolic sodium hydroxide, sodium methoxide or the like, and thendistilling the mixture to dryness. When the reaction solvent issubstantially water-soluble, the base wash may be performed after thesolvent has been removed, or the distillation may be omitted in favor ofprecipitation of the steroid from the mixture by the addition of a largevolume of water, preferably containing enough base to neutralize thecatalyst.

Treatment of a 3-cyclic ketalized3-keto-ll-oxygenated-4,17(20)-pregnadiene-2l-oic acid or esterj thereof(II) with a reducing agent, such as lithium aluminum hydride or thelike, is productive of a 3-cyclic ketalizedl1,2l-dihydroxy-4,l7(20)-pregnadiene-3-one (III) wherein the ll-hydroxygroup has the alpha or beta configuration.

The lithium aluminum hydride reduction is usually carried out by addinga solution of the selected 3-cyclic ketalized l l-oxygenated-4,l7(20)-pregnadiene-2l-oic acid or alkyl ester thereof (II) in an organicsolvent, which is non-reactive under the conditions of the reaction, toa lithium aluminum hydride solution or suspension in ether. Othersolvents which may be used include dioxane, tetrahydrofuran, or thelike, as well as other solvents commonly used in lithium aluminumhydride reductions. When ether is used, the reaction is usually carriedout at a temperature between about room temperature and the boilingpoint of the ether, although temperatures substantially below roomtemperature may sometimes be successfully employed, e. g., from aboutminus ten to about plus ten degrees centigrade, such temperaturesometimes resulting in higher yields of desired product.

Lithium aluminum hydride is usually employed in a substantial chemicalequivalent excess to ensure optimum yields of desired product. When thesteroid and lithium aluminum hydride have been thoroughly mixed and theheat of reaction has subsided, the reaction is essentially complete.Continued stirring or heating or both are usually employed, however, toensure completeness of reaction. The excess lithium aluminum hydride andany organolithium complex present is decomposed by the careful additionof water to the reaction mixture. If the reaction mixture is maintainedat an alkaline pH, that is, if no acid is added during the decompositionof the lithium aluminum hydride or subsequent thereto, or if an organicacid such as acetic acid, propionic or other weaker acid is employed inthe hydrolysis, the corresponding 3-cyclic ketalizedl1,21-dihydroxy-4,l7(20)- pregnadiene-3-one can be isolated directlyfrom the reaction mixture. This is frequently advantageous since theketalized steroid is sometimes more readily purified than the free ketosteroid. Separating the organic phase from the aqueous phase of thedecomposed reaction mixture and then distilling the solvent therefromleaves a distillation residue consisting essentially of the desiredprodnet. The resulting 3-cyclic ketalized 11,21-dihydroxy-4,l7(20)-pregnadiene-3-one (III) may be isolated as described above, forexample, or further reacted without isolation as more fully disclosedhereinafter.

The free 3-ketone, an 1l,2l-dihydroxy-4,l7(20)-pregnadiene-3-one (IV),is prepared by treatment of a solution of the crude or purified 3-cyclicketalized 11,21-dihydroxy-4,l7(20)-pregnadiene-3-one in an organicsolvent with dilute aqueous acid, preferably a mineral acid such as, forexample, hydrochloric or sulfuric acid, usually at about roomtemperature, for from about onehalf hour to about 72 hours. The amountof the acid employed is usually from about a trace to a large molarexcess and concentrations from extremely dilute to fairly concentratedmay be employed since the acid acts only as a catalyst for thehydrolysis. When the hydrolysis product islla,2l-dihydroxy-4,l7(20)-pregnadiene-3-one, the hydrolysis of the3-cyclic ketal can be carried out under fairly rigorous conditions, i.0., with fairly strong concentration of acid and at temperaturessubstantially above room temperature, whereas when the hydrolysisproduct is llfl,2l-dihydroxy-4,17(20)-pregnadiene-3-one, the hydrolysisreaction is preferably carried out at about room temperature and in thepresence of more dilute acid since the llfl-hydroxy group has a tendencyto dehydrate in the presence of acid. The reaction temperature andreaction time required to complete the hydrolysis reaction is somewhatdependent upon the particular 3-ketal group present in the steroid.Isolation of the free 1l,2l-dihydroxy-4,l7(20)-pregnadiene-3-one isconveniently achieved by neutralizing the reaction mixture, distillingthe solvent therefrom, or adding a large volume of water thereto if thesolvent is water-miscible, and then removing the thus-precipitatedproduct. The thus-isolated 1l,21-dihydroxy-4,17(20)-pregnadiene-3-one(IV), after drying, usually does not require purification for subsequentreactions if the starting 3-cyclic ketal was pure.

A convenient procedure for obtaining an11,21-dihydroxy-4,17(20)-pregnadiene-3-one (IV) from a 3-keto-1l-oxygenated-4,17(20)-pregnadiene-21-acid or alkyl ester thereof (I)involves reaction the starting3-keto-1loxygenated-4,17(20)-pregnadiene-2l-acid or alkyl ester thereof,protected at the 3 position with a 3-ketal, preferably a 3-ethyleneglycol ketal (II, R and R'=H, n: .1), with a reducing agent, e. g.,lithium aluminum hydride, according to the procedure described above andthen, after decomposing the excess lithium aluminum hydride with water,hydrolyzing the B-ketal of the reaction product without isolation. Thisis conveniently accomplished by adding a mineral acid, preferablyhydrochloric acid, to the reaction mixture to render the mixtureslightly acidic, and thereafter stirring the acidic reaction mixture forfrom about one-half hour to about 72 hours to remove the protectinggroup at the 3 position. Isolation of the thus-produced11,21-dihydroxy-4,17(20)- pregnadiene-3one is conveniently achieved byremoving the organic layer from the reaction mixture, washing said layerwith water or base, and then distilling the solvent therefrom to leaveas distillation residue the essentially pure11,21-dihydroxy-4,l7(20)-pregnadiene-3- one (IV).

The following examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting.

PREPARATION 1.Somtnvr ENOLATE OF IIzx-HYDROXY-ZI-ETHOXYOXALYLPROGESTERONE PREPARATION 2.-SDIUM ENoLATE or1l/3-HYDROXY-21- ETHOXYOXALYLPROGESTERONE One hundred and forty-four(144) milligrams (6.25 millimoles) of sodium was dissolved in fivemilliliters of absolute ethanol under an atmosphere of nitrogen and tothis solution were added eight milliliters of benzene and 0.8 milliliter(0.9 gram; 6.15 millimoles) of ethyl oxalate. The mixture was cooled inan ice-water bath and a solution of 1.99 grams (6.03 millimoles) ofllfl-hydroxyprogesterone, dissolved in five milliliters of absoluteethanol and mixed with 25 milliliters of dry benzene, was added in aslow'stream to the stirred solution. The reaction mixture was stirred atroom temperature for 2.5 hours at the end of which time a 100-milliliterportion of ether was added followed by another 100-millliter portion ofether one hour later. The thus-produced pale yellow precipitate wasfiltered and washed with ether. The yield of11B-hydroxy-21ethoxyoxalylprogesterone was 1.68 grams (62 percent).

PREPARATION 3.SOD1UM ENOLATE OF 11-KETO-21- ETHOXYOXALYLPROGESTERONE Toa mixture of 3.4 milliliters of a 3.4 Normal methanolic sodium methoxidesolution (0.0116 mole), 0.45 milliliter of absolute ethanol, and twentymilliliters of dry benzene, said mixture previously having beendistilled until eight milliliters of distillate had been collected andthen cooled, was added 2.3 milliliters (0.0151 mole) of ethyl oxalateand a solution of 3.28 grams (0.01 mole) of ll-ketoprogesterone in 38milliliters of dry benzene. The solution became turbid and a yellowprecipitate formed. The reaction mixture was stirred for ninety minutes,55 milliliters of ether was then added thereto, and stirring wascontinued for sixty minutes, whereafter a -mi1liliter portion of etherwas added thereto. The thus-formed yellow precipitate of the sodiumenolate of 11-keto-21-ethoxyoxalylprogesterone was filtered, washed withseveral fifty-milliliter portions of ether, and after drying found toweigh 3.65 grams. The ether wash contained 0.54 gram of unreactedll-ketoprogesterone. The yield of the sodium enolate ofll-keto-2l-ethoxyoxalylprogesterone was 81 percent of the theoretical orpractically quantitative calculated on the reacted ll-ketoprogesterone.The presence of a sodium enolate was verified by the extreme solubilityof the product in water and by a positive ferric chloride test for enolsas exhibited by the formation of a bright red color when the product wasdissolved in alcoholic and aqueous ferric chloric solutions.

PREPARATION 4.-11ot-HYDROXY-Z1,21-DIBROM0-21- ETI-IOXYOXALYLPROGESTERONEPREPARATION 5 .1 1/i-nYnRoxY-2 1,2 1-D1BRoMo-21-ETHOXYOXALYLPROGESTERONE In exactly the same manner as described inPreparation 4, contacting the sodium enolate of llfi-hydroxy-21-ethoxyoxalylprogesterone with approximately two molar equivalents ofbromine is productive of1LB-hydroxy-Z1,2l-dibrorno-Z1-ethoxyoxalylprogesterone.

PREPARATION 6.1 1-RETo-21,21-DrBoMo-21- ETHOXYOXALYLPROGESTERONE To astirred solution of 4.50 grams (0.01 mole) of the sodium enolate of11-keto-21-ethoxyoxalylprogesterone and two grams of potassium acetatein seventy milliliters of glacial acetic acid was added 3.09 grams 1.00milliliter; 0.0193 mole) of bromine dropwise at room temperature. Whenthe addition was complete, the reaction mixture was mixed with a largevolume of water. The aqueous layer was then decanted from theprecipitated viscous yellow product which was thereafter dissolved inalcohol and re-precipitated as a white solid by the dropwise addition ofwater. The yield of thus-produced 11-keto-21,21-dibromo-Z1-ethoxyoxalylprogesterone, after filtering and drying, was 4.0grams, a yield of seventy percent of the theoretical.

PREPARATION 7 .3 KETO1 1aHYDROXY-4,17(20)- PREGNADIENE-Zl-QIC Acm METHYLESTER To a solution of 29.4 grams (0.05 mole) oflla-hydroxy-21,21-dibromo-21-ethoxyoxalylprogesterone in 550 millilitersof methanol was added a solution of 16.5 grams (0.3 mole) of sodiummethoxide in 500 milliliters of methanol. The reaction mixture wasmaintained at about 25 degrees centigrade for sixteen hours whereafteran equal volume of water was added thereto and the whole was extractedwith about equal portions of first benzene and then two portions ofmethylene chloride. The combined extracts were dried with anhydroussodium sulfate and thereafter distilled to remove the solvent therefrom.The distillation residue was dissolved in 500 milliliters of methylenechloride and chromatographed over 875 grams of Florisil syntheticmagnesium silicate. The column was developed with 1,250-milliliterportions of solvents of the following composition and order: four ofmethylene chloride plus five percent acetone, four of methylene chlorideplus ten percent acetone, four of methylene chloride plus fifteenpercent acetone, two of methylene chloride plus twenty percent acetone,and finally, two of acetone. The methylene: chloride plus ten percentacetone eluates and the first methylene chloride plus fifteen percentacetone eluate were combined and the solvent distilled therefrom. Theseven grams of distillation residue was recrystallized from a mixture ofethyl acetate and Skellysolve B hexane hydrocarbons to pressure toremove the benzene.

yield crystalline 3-keto- 11a-hydroxy-4, 17 (20) -pregn ad1ene-21-oicacid methyl ester, melting at 205 to 210 degrees centigrade.

Analysis:

Calculated for C22H3004 s- C, 73.75; H, 8.48 Found C, 73.77; H, 8.38 C,74.10; H, 8.59

Similarly, other 3 keto-11a-hydroxy-4,17(20)-pregnadiene-21-oic acidesters are prepared wherein the ester is methyl, propyl, butyl, amyl,hexyl, heptyl, octyl, or the like, by replacing the sodium methoxide inmethanol used in the above-described reaction by the selectedalkali-metal alkoxide in an alkanol.

PREPARATION 8.--3 -KETO-1 1 fiHYDROXY-4, 1 7 20 PREoNAnIENE-21-o1c ACIDETHYL EsTER PREPARATION 9.3,1 1-DIKETO-4, 17 (20) -PREGNADIENE-21 oIcACID METHYL EsTER To a solution of 5.90 grams (0.01 mole) of 11-keto-21,21 dibromo-21-ethoxyoxalylprogesterone, obtained according to themethod given in Preparation 7, in 150 milliliters of methanol, was added3.24 grams (0.06 mole) of commercial grade sodium methoxide. Theresulting admixture was maintained for three hours at about 25 degreescentigrade, whereafter the Whole was diluted with water and thenextracted with two portions of methylene chloride. The methylenechloride extracts were dried with anhydrous sodium sulfate and thesolvent was thereafter distilled at atmospheric pressure, leaving aquantitative yield of 3.60 grams of 3,11-diketo-4,l7(20)-pregnadiene-21-oic acid methyl ester as an oil. This oil wasdissolved in fifty milliliters of benzene and chromatographed over acolumn of 170 grams of Florisil syntheticmagnesium silicate. The columnwas developed with 400-milliliter portions of solvent of the followingcomposition and order: three portions of methylene chloride, fiveportions of methylene chloride plus five percent acetone, and oneportion of acetone. The methylene chloride plus five percent acetoneeluates were combined and the solvent was removed therefrom leaving 1.5grams of: crystalline 3,11-diketo-4,17(20)-pregnadiene-21-oic acidmethyl ester which, after crystallization from acetone and Skellysolve Bhexane hydrocarbons, melted at 213 to 214 degrees centigrade.

Analysis:

Calculated for C2zH2sO4 C, 74.17; H, 7.92 Found C, 74.37; H, 8.21

Similarly, other 3,11-diketo-4,17(20)-pregnadiene-21- oic acid estersare prepared wherein the ester is loweralkyl, e. g., ethyl, propyl,butyl, amyl, hexyl, heptyl, octyl, or the like, by replacing the sodiummethoxide in methanol used in the above-described reaction with theselected alkali-metal alkoxide in an alkanol.

PREPARATION 10.3,1 1-DIKETO-4, 17 (20) -PREGNADIENE- 21-o1c AcIn Inexactly the same manner as given in Preparation 9, 3,11 diketo 4,l7(20)pregnadiene 21 oic acid was prepared from the sodium enolate ofll-keto-Zlethoxyoxalylprogesterone by substituting 3.4 grams (0.06 mole)of potassium hydroxide in ten milliliters of water for the sodiummethoxide used in the abovedescribed reaction, thus producing thepotassium salt of the desired acid. The3,1l-diketo-4,17(20)-pregnadiene- 2l-oic acid was isolated by washingthe reactioh mixture with methylene chloride, acidifying with dilutehydrochloric acid and extracting the thus-produced oily precipitate withbenzene. The benzene extract was washed with water, dried, andthereafter distilled at reduced The residual 3,11-diketo 4,l7(20)pregnadiene 21 oic acid, after several crystallizations, melted at 255to 260 degrees ..centigrade.

PREPARATION 1 1 .3 -KETO-1 1cz-HYDROXY-4, 1 7 (20 PREoNAnIENE-21-oIcAcn) In exactly the same manner as given in Preparation7, 3 keto 11ozhydroxy 4,l7(20) pregnadiene 21- oic acid is prepared from11a-hydroxy-21,21-dibromo- 2l-ethoxyoxalylprogesterone by substituting3.4 grams (0.6 mole) of potassium hydroxide for the sodium methoxide inthe above-described reaction. 3-keto-11a-hydroxy 4,l7(20) pregnadiene 21oic acid is isolated from the reaction mixture by adding water thereto,washing with methylene chloride, and then acidifying the washed reactionmixture. The precipitated 3-keto-11ahydroxy 4,l7(20) pregnadiene 21 oicacid is purified by separating the precipitated product andcrystallizing the dried product from a solvent such as, for Example,acetone plus Skellysolve B hexane hydrocarons.

PREPARATION 12.-3-KETo-11B-IIYDRoxY-4,17(20)- PREGNADIENE-Z l-oIc ACIDIn the same manner as described in Preparation 11, 3 keto 116 hydroxy4,l7(20) pregnadiene 21- oic acid is prepared by reacting11B-hydr0xy-21,21-dibromo-2l-ethoxyoxalylprogesterone with a base,preferably an alkali-metal hydroxide or other alkali-metal base, in thepresence of water, and thereafter acidifying the reaction mixture, aswith dilute mineral acid, e. g., hydrochloric, sulfuric acid, or thelike, to produce the free 3 keto 11p hydroxy 4,l7(20) pregnadiene 21-oic acid.

Example 1.3-Ethylenc glycol ketal of 3-ket0-11a-hydroxy 4,l7(20)pregnadiene 21 oic acid methyl ester To a solution of 1.5 grams (0.0042mole) of 3-keto- 11a hydroxy 4,l7(20) pregnadiene 21 oic acid methylester in milliliters of benzene were added 7.5 milliliters of ethyleneglycol and 0.150 gram of paratoluenesult'onic acid and the Whole wasthen refluxed and stirred for 5.5 hours. The cooled solution was thenwashed with 100 milliliters of a one percent aqueous sodium bicarbonatesolution whereafter the washed solution was poured over a column of 200grams of Florisil magnesium silicate. 200milliliter portions of solventsof the following composition and order: four of Skellysolve B hexanehydrocarbons plus four percent acetone, four of Skellysolve B plus sixpercent acetone, four of Skellysolve B plus ten percent acetone, four ofSkellysolve B plus fifteen percent acetone, and finally, two portions ofacetone. The last Skellysolve B plus ten percent acetone eluate and thefirst three Skellysolve B plus fifteen percent acetone eluate fractionswere combined, the solvent removed therefrom, and the residual3-ethylene glycol ketal of 3-k6tO-11czhydroxy 4,l7(20) pregnadiene 21oic acid methyl ester was recrystallized from a mixture of ethyl acetateand Skellysolve B hexane hydrocarbons to give 1.46 grams of crystalsmelting at 181 to 185 degrees centigrade. Further recrystallization ofthese crystals gave 1.25 grams of the 3-ethylene glycol ketal of3-keto-11ahydroxy 4,17(20)-pregnadiene-21-oic acid methyl ester meltingat 184 to 188 degrees centigrade.

Example 2.3-Ethylene glycol ketal of 3-ket0-11a-hydroxy 4,] 7(20)pregnadiene 21 oic acid ethyl ester Following the procedure described inExample 1, the reaction of 3-keto-11a-hydroxy-4,17(20)-pregnadiene-2l-oic acid ethyl ester with more than about one molar equivalent ofethylene glycol, in the presence of paratoluenesulfonic acid, isproductive of the 3-ethylene glycol ketal of3-keto-11a-hydroxy-4,17(20)-pregnadiene- 21-oic acid ethyl ester.

Similarly, the 3-ethylene glycol ketal of other esters of 3 keto 11hydroxy 4,l7(20) pregnadiene 21 oic acid such as, for example, thepropyl, butyl, amyl, hexyl, heptyl, octyl, or like ester, is prepared byreacting the selected alkyl ester of 3-keto-llot-hydroxy-4,l7(20)-pregnadiene-Zl-oic acid with ethylene glycol according to the methoddescribed in Example 1 in the presence of an The column was developedwith.

acid catalyst such as, for example, hydrogen chloride, binzene sulfonicacid, para-toluenesulfonic acid, or the li e.

Example 3.3-Elhylene glycol ketal of S-keto-ZIa-hydroxy 4,17(20)pregrradiene 21 oic acid methyl ester.

A mixture of 7.5 grams (0.0215 mole) of 3-keto-llahydroxy 4,17( 20)pregnadiene 21 oic acid methyl ester, 37.5 milliliters of ethyleneglycol, and 075 gram of para-toluenesulfonic acid in 750 milliliters ofdry benzene was refluxed with concomitant removal of the water ofreaction for 5.5 hours. The cooled mixture was then stirred for fiveminutes with 500 milliliters of a one percent aqueous sodium bicarbonatesolution whereafter the benzene layer was removed, dried over anhydroussodium sulfate and the solvent then removed from the dried solution bydistillation at reduced pressure. The residual solids were dissolved infifty milliliters of hot ethyl acetate to which was then added 400milliliters of hot Skellysolve B hexane hydrocarbons. The mixture wasthen cooled to room temperature and then chilled in a refrigerator atfour degrees centigrade for four hours. The precipitated solids werefiltered and dried in vacuo to yield 5.8 grams of the 3-ethylene glycolketal of 3-keto- 11a hydroxy 4,l7(20) pregnadiene 21 oic acid methylester melting at 175 to 182 degrees centigrade. Recrystallization ofthis material from ethyl acetate and Skellysolve B raised the meltingpoint to 183 to 186 degrees centigrade. The rotation of the product [a]was plus 23 degrees in acetone.

Example 4.3-Trimethylene glycol ketal of 3-keto-11ahydroxy 4,1 7(20)pregnadiene 21 oic acid methyl ester In the same manner as described inExample 1, reacting 3 keto 11a hydroxy 4,17(20) pregnadiene 21- oic acidmethyl ester with trimethylene glycol in the presence ofpara-toluenesulfonic acid is productive of the 3- trirnethylene glycolketal of 3,11-diketo-4,17(20)-pregnadiene-Zl-oic acid methyl ester.

Similarly, other 3-ketals of the methyl and other esters of 3 keto 11ahydroxy 4,l7(20) pregnadiene 21- oic acid and3-keto-llB-hydroxy-4,l7(20)-pregnadiene- 2l-oic acid are produced byreaction of a selected ester of one of the above-described steroidacids, especially the methyl, ethyl, propyl, isopropyl, butyl, amyl,hexyl, heptyl, or octyl ester, with a glycol such as, for example,ethylene glycol, propylene glycol, trimethylene glycol, an alkylsubstituted ethylene glycol, propylene glycol, or trimethylene glycol,or the like, in the presence of an acid catalyst such as, for example,para-toluenesulfonic acid, hydrogen chloride, sulfuric acid, or thelike.

Example .-3-Ethylene glycol ketal of 3-ket0-11B-hydroxy 4,17 pregnadiene21 oic acid methyl ester The 3-ethylene glycol ketal of3-keto-11/i-hydroxy- 4,17(20)-pregnadiene-2l-oic acid methyl ester isprepared by mixing 3-keto-llfi-hydroxy-4,l7(20)-pregnadiene-Z-oic acidmethyl ester with a large volume of ethylene glycol, thereby dissolvingthe steroid therein, and then adding a catalytic amount ofpara-toluenesulfonic acid at room temperature. After allowing themixture to remain at room temperature for 48 hours, the catalyst isneutralized with sodium bicarbonate and the ethylene glycol removed bydistillation at room temperature at high vacuum. Dissolving the residuein chloroform which is then washed with dilute sodium bicarbonate andthen water, dried, and the chloroform evaporated therefrom, leaves aresidue of the 3-ethylene glycol ketal of 3 keto 11B hydroxy 4,17(20)pregnadiene-2l-oic acid methyl ester which, when crystallized repeatedlyfrom acetone and Skellysolve B hexane hy drocarbons, melts at 167 to 169degrees centigrade and has an [(11 of plus four degrees.

Analysis:

Calculated for C24H34O4 C, 71.61; H, 8.51 Found C, 71.63; H, 8.78

Example 6.-3-Ethylene glycol ketal of 3,11-diket0-4,17(20)-pregnadiene-21-oic acid methyl ester To a solution of 1.5 grams(0.0042 mole) of 3,11- diket0-4,17(20)-pregnadiene-2l-oic acid methylester dissolved in 150 milliliters of benzene was added 7.5 millilitersof ethylene glycol and 0.150 gram of paratoluenesulfonic acid and thewhole was then heated with stirring at the reflux temperature of thereaction mixture for 5.5 hours. The cooled reaction mixture was washedwith milliliters of a one percent aqueous sodium bicarbonate solution.The benzene layer was then poured on a column of grams of Florisilsynthetic magnesium silicate. The column was developed with 100-milliliter portions of solvents of the following composition and order:eight portions of methylene chloride and three portions of methylenechloride plus four percent acetone. The methylene chloride eluatescontained 1.08 grams of the 3-ethylene glycol ketal of3,11-diketo-4,17(20)- pregnadiene-Zl-oic acid methyl ester, which uponrecrystallization from a mixture of ethyl acetate and Skellysolve Bhexane hydrocarbons melted at 188 to 190 degrees centigrade and had theanalysis given below. The methylene chloride plus four percent acetoneeluates contained 0.390 gram of pure starting 3,11-diket0-4,17(20)-pregnadiene-Zl-oic acid methyl ester. The yield of product was 87percent of the theoretical calculated on the amount of starting steroidwhich reacted.

Analysis:

Calculated for C24H32O5 C, 71.94; H, 8.05 Found C, 71.90; H, 7.95

Similarly, the 3-ethylene glycol ketals of other alkyl esters of3,1l-diketo-4,17(20)-pregnadiene-2l-oic acid such as, for example, themethyl ester, the ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, orlike ester, especially the 3-ethylene glycol ketal of3,11-diketo-4,17(20)-preg nadiene-2l-oic acid methyl ester, are preparedby reacting the selected alkyl ester of 3,ll-diketo-4,l7(20)-pregnadiene-Zl-oic acid with ethylene glycol according to the methoddescribed in Example 6 in. the presence of an acid catalyst such as, forexample, anhydrous hydrogen chloride, benzene sulfonic acid,para-toluenesulfonic acid, or the like.

Example 7 .3-Ethylene glycol ketal of 3-ket0-11a-hydr0xy-4,17(20)-pregnadiene-21-oic acid The 3-ethylene glycol ketal of3-keto-1la-hydroxy- 4,17(20)-pregnadiene-2l-oic acid is prepared byallowing a mixture of 3-keto-11a-hydroxy-4,17(20)-pregnadiene 2l-oicacid and a large molar excess of ethylene glycol, to which has beenadded a small amount of paratoluenesulfonic acid, to stand at roomtemperature for 48 hours. The excess ethylene glycol is then distilledat reduced pressure and the distillation residue washed with dilutesodium hydroxide. The aqueous layer is then separated and acidifiedthereby precipitating 3-ethylene glycol ketal of 3-keto-11a-hydroxy-4,17(20)-pregnadiene-Zl-oic acid along with small amounts of startingmaterial which is separated therefrom by repeated crystallization of themixture. The material not extracted with the dilute base contains somesteroid Whose acid radical is esterified by the ethylene glycol.Treating this material with dilute sodium hydroxide in methanol andwater followed by liberation of the free acid by neutralization of themixture with very dilute: acid is productive of the 3-ethylene glycolketal of 3-keto-lla-hydroxy-4,l7(20)-pregnadiene-2l-oic acid which maybe purified in the same manner as the precipitated reaction productdescribed above.

Similarly, other 3-glycol ketals of 3-k6tO-11a-hYdI'OXY-4,17(20)-pregnadiene-2l-oic acid are prepared by substituting theselected 3-glycol ketal of3-keto-l1a'hydroxy-4,17(20)-pregnadiene-2l-oic acid for the 3- ethyleneglycol ketal thereof in the above-described reaction.

Example 8. 3-Ethylene glycol ketal 0f 3-ket0-11flhydr0xy-4,17(20)-pregr1adiene-21-0ic acid tuting 3keto-1l/8-hydroxy-4,l7(20)-pregnadiene-2l-oic alcid as the startingmaterial in the reaction described t erein.

Example 9.-3-Trimethylene glycol ketal of 3,]1-dikef0- 4,17(20)-pregnadiene-2I-oic acid In the same manner as described in Example 7,reacting 3,11-diketo-4,17(20)-pregnadiene-21-oic acid with trimethy-leneglycol in the presence of an acid catalyst is productive of the3-trimethylene glycol ketal of 3,11- diketo-4,17(ZO)-pregnadiene-21-oicacid.

Similarly, other 3-ketals of the compounds of Examples 1 to 9 areproduced by the reaction of the selected acid or ester thereof,especially the methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, oroctyl ester thereof, with a glycol such as, for example, ethyleneglycol, propylene glycol, trimethylene glycol, an alkyl substitutedethylene glycol, propylene glycol, or trimethylene gylcol, or the like,in the presence of an acid catalyst, such as, for example,para-toluenesulfonic acid, hydrogen chloride, sulfuric acid or the like.

It is to be understood that the invention is not to be limited to theexact details or exact compounds shown and described as obviousmodifications and equivalents will be apparent to one skilled in the artand the invention is therefore to be limited only by the scope of theappended claims.

We claim:

1. A compound represented by the following formula:

wherein R is selected from the group consisting of an az-hYdIOXY group,a fi-hydroxy group, and a ketonic oxygen, wherein R, R and R areselected from the group consisting of hydrogen and hydrocarbon radicalscontaining-less than nine carbon atoms and n is selected from the wholenumbers Zero and one and wherein R" and R together contain less than 9carbon atoms.

Cit

12 2. A compound represented by the following formula:

CHa

C 0 0l0wer-alkyl H ll I wherein n is a whole number from two to three,inclusive.

3. A compound of claim 2 wherein n is 2. 4. A compound represented bythe following formula:

C O 0-lower alkyl No references cited.

1. A COMPOUND REPRESENTED BY TE FOLLOWING FORMULA: